REGISTERING MIFEPRISTONE FOR INDICATIONS OTHER THAN FIRST TRIMESTER ABORTION: A LANDSCAPE ANALYSIS REPORT PROJECT REPORT Mifepristone indications brief PAGE 1 BACKGROUND AND JUSTIFICATION Mifepristone is an antiprogestin that blocks the activity of progesterone, the hormone which is needed to maintain a pregnancy. Mifepristone also plays a role in softening and dilating the cervix and thus has been used for cervical ripening prior to medical procedures. It is most commonly known for its use in combination with the drug misoprostol to induce abortion. The safety and efficacy of mifepristone for first trimester abortion has been well-documented and its use for this purpose has expanded greatly over the past two decades. Global availability of the commodity “mifepristone” has also expanded; there are now WHO pre-qualified products, three SRA approved products, and two SRA approved combi-packs. Nonetheless, while mifepristone is registered more than 68 countries for first trimester abortion, it is not always available or used. Additionally, given its antiprogestin and cervical ripening properties, mifepristone can be used for alternative indications both in reproductive health and other therapeutic areas. However, there have been limited efforts to pursue labeling for non-abortion indications (although, the innovator product, Mifegyne®, is registered for four indications). For these reasons, mifepristone is a highly underutilized medication, specifically for improving women’s health, and this underutilization threatens market sustainability. Mifepristone registration for indications other than first trimester abortion has the potential to be a major game changer by creating the framework to facilitate greater commodity access in restricted settings. Furthermore, expanding registration has the potential to move mifepristone from its status as an “abortion drug” used only by abortion providers to being known as a medication for improving women’s health used by a broad range of health care providers. More indications could also increase demand, and thus improve market sustainability, which may in turn generate interest by pharmaceutical companies to pursue its marketing and distribution, including private sector distributors and social marketing organizations (SMOs). Gynuity Health Projects has worked for almost two decades to develop clinical evidence on the safety and efficacy of mifepristone for indications outside of first trimester abortion. This work serves as a strategy for expanding mifepristone access in countries with restrictive abortion laws or increasing the market in countries where mifepristone is registered for first trimester abortion but remains underutilized. Indications include early pregnancy loss, intra-uterine fetal death (IUFD), cervical ripening, second trimester abortion for maternal health or fetal indication, and menstrual regulation. These indications are legal and less politically and culturally sensitive in most relevant jurisdictions, and, in turn, registration may not pose the same problems as have been encountered for registration for first trimester elective abortion. Further, registration provides an entry point for mifepristone to be added to national drug registries, stocked in hospitals and other health care facilities, and integrated into health care systems. We conducted a landscape analysis of the registration and marketing feasibility for alternative mifepristone indications in six countries with limited abortion availability (legal and otherwise), global representation, and some of which had a sizeable potential market share. The goal was to identify the indication(s) with the greatest promise for registration and recommendations for what steps would help to move registration forward successfully as well as ensure availability and use post-approval. Mifepristone indications brief PAGE 2 SELECTION OF ORGANIZATIONS AND KEY INFORMANTS FOR GLOBAL STAKEHOLDER INTERVIEWS We conducted interviews with eight organizations (pharmaceutical companies, international NGOs, and social marketing organizations) to assess their interest in the alternative indications, geographic and market priorities, and perceived barriers to pursuing registration for additional mifepristone indications. Stakeholder organizations play various roles related to mifepristone availability and use—from registration to distribution to marketing. Country selection for national-level assessment Country-level assessments were conducted in six countries (see text box). Countries were selected to ensure regional representation – with at least one country from West Africa, one from Latin America, one from East Africa, one from South Asia and one from Eastern Europe/Caucuses. Countries selected fell into at least one of the following categories: 1) no mifepristone product currently registered for any indication, 2) limited legal abortion status, 3) known interest in exploring mifepristone registration for indications other than first trimester abortion. There was also an interest in selecting countries where abortion is legally permitted and mifepristone is or has been registered, but where the market is not stable. Key stakeholders represented a range of groups involved in reproductive health care including staff from ministries of health or drugs and regulatory bodies, health care providers and national staff of international NGOs. COUNTRIES SELECTED AND NUMBER OF INTERVIEWS PER COUNTRY Burkina Faso (2) Colombia (4) Kenya (2) Latvia (3) Pakistan (3) Senegal (3) LEARNINGS FROM GLOBAL STAKEHOLDER INTERVIEWS Interest in registering mifepristone for alternative indications Stakeholder organizations were overwhelmingly supportive of registering mifepristone for alternative indications. Most stakeholders were aware of the four indications that were the focus of this assessment (early pregnancy loss, IUFD, second trimester abortion, and cervical ripening). There was interest in registering all four indications and no consensus as to which indication would be most promising. Interestingly, one stakeholder stated that future registration efforts should be focused on registering the combi-pack, not just mifepristone. The reason they cited was that mifepristone is used in conjunction with misoprostol for most indications other than first trimester abortion, including second trimester abortion, IUFD, and missed abortion. A distributor drew attention to the disparate expiration dates of mifepristone and misoprostol as a downside to co-packaging. Stakeholders were also widely aware of mifepristone’s other reproductive health indications, such as for emergency contraception, menstrual regulation, and treatment of endometriosis and fibroids. They expressed interest in knowing more about the evidence available on these indications and exploring opportunities for registration. Finally, stakeholders were aware that mifepristone can be used for indications beyond reproductive health, like Cushing’s syndrome. However, for those indications, the pill size may be different. For this reason, such indications were not the focus of this assessment. Yet, given potential interest in these indications, relevant stakeholders may consider convening an expert meeting to explore a path forward for registration. Mifepristone indications brief PAGE 3 GEOGRAPHIC PRIORITIES FOR REGISTRATION Sub-Saharan Africa, West Africa specifically, was most frequently mentioned as a priority by nearly all organizations. This regional priority likely reflects both the legal context for abortion (which limits opportunities for mifepristone registration for first trimester abortion) and donor priorities and funding. Several stakeholders specifically indicated that geographic priority is largely based on available funds and funder priorities. Further, most stakeholders indicated that their geographical priorities would align with regions of the world where abortion is most restricted. Two organizations expressed interest in the Latin America and Caribbean (LAC) market, Mexico, Colombia and Argentina specifically. LAC could be a promising market, especially for commercial entities. Barriers to registration Barriers to registration fall into three categories: 1) political/legal, 2) financial, and 3) knowledge. Political barriers relate primarily to legal restrictions on abortion and the widespread understanding that mifepristone is an abortion drug. Several key informants from both Social Marketing Organizations and manufacturers mentioned both a lack of political will and significant regulation burdens. One key informant did emphasize that the fact that mifepristone can be used for abortion should not determine the success of registration for non-abortion indications. Whether or not mifepristone is used for but not approved for abortion is related to regulations regarding distribution. Additionally, even if mifepristone is approved for abortion under limited circumstances, this does not mean that it will be made available for unapproved uses, since it is possible to restrict distribution channels to approved indications. This critical distinction, between approval and availability, needs to be reflected in registration strategies and approaches. Financial barriers are also relevant to the cost of registration and the sustainability of the market post- registration. There can be significant cost to supporting activities needed for registration. One issue raised by manufacturer stakeholders was the preparation of the regulatory dossier, even when clinical and other data exist. In